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Analysis of Full and Partial Agonists Binding to 2-Adrenergic Receptor Suggests a Role of Transmembrane Helix V in Agonist-
 

Summary: Analysis of Full and Partial Agonists Binding to 2-Adrenergic
Receptor Suggests a Role of Transmembrane Helix V in Agonist-
Specific Conformational Changes
Vsevolod Katritch1, Kimberly A. Reynolds1, Vadim Cherezov1, Michael A. Hanson1,
Christopher B. Roth1, Mark Yeager2,3, and Ruben Abagyan1
1Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,
CA 92037 USA
2Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA
92037 USA
3Department of Molecular Physiology and Biological Physics, University of Virginia Health System, PO Box
800736, Charlottesville, VA 22908-0736
Abstract
The 2.4 crystal structure of the 2-adrenergic receptor (2AR) in complex with the high-affinity
inverse agonist (-)-carazolol provides a detailed structural framework for the analysis of ligand
recognition by adrenergic receptors. Insights into agonist binding and the corresponding
conformational changes triggering GPCR activation mechanism are of special interest. Here we show
that while the carazolol pocket captured in the 2AR crystal structure accommodates (-)-isoproterenol
and other agonists without steric clashes, a finite movement of the flexible extracellular part of TM-
V helix (TM-Ve) obtained by receptor optimization in the presence of docked ligand can further
improve the calculated binding affinities for agonist compounds. Tilting of TM-Ve towards the

  

Source: Abagyan, Ruben - School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego

 

Collections: Biology and Medicine